tbuckley/cabot-search huggingface dataset:
Intelligent design of polymer nanogels for full-process sensitized radiotherapy and dual-mode computed tomography/magnetic resonance imaging of tumors
Authors: Changchang Zhang, Wenzhi Tu, Xuming Chen, Bing Xu, Xin Li, Chaolei Hu, Mingwu Shen, Shaoli Song, Chunjuan Jiang, Shengyu Yao, Andrij Pich, Yong Liu, Xiangyang Shi
Journal: Theranostics (2022)

Rationale: Development of intelligent radiosensitization nanoplatforms for imaging-guided tumor radiotherapy (RT) remains challenging.We report here the construction of an intelligent nanoplatform based on poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with gold (Au) and manganese dioxide (MnO2) nanoparticles (NPs) for dual-mode computed tomography (CT)/magnetic resonance (MR) imaging-guided "full-process" sensitized RT of tumors.Methods: PVCL NGs were synthesized via precipitation polymerization and in situ loaded with Au and MnO2 NPs.The created PVCL-Au-MnO2 NGs were well characterized and systematically examined in their cytotoxicity, cellular uptake, intracellular oxygen and •OH production, and cell cycle arrest in vitro, evaluated to disclose their RT sensitization effects of cancer cells and a tumor model, and assessed to validate their dual-mode CT/MR imaging potential, pharmacokinetics, biodistribution, and biosafety in vivo. Results:The formed PVCL-Au-MnO2 NGs with a size of 121.5 nm and good stability can efficiently generate reactive oxygen species through a Fenton-like reaction to result in cell cycle distribution toward highly radiosensitive G2/M phase prior to X-ray irradiation, sensitize the RT of cancer cells under X-ray through the loaded Au NPs to induce the significant DNA damage, and further prevent DNA-repairing process after RT through the continuous production of O2 catalyzed by MnO2 in the hybrid NGs to relieve the tumor hypoxia.Likewise, the in vivo tumor RT can also be guided through dual mode CT/MR imaging due to the Au NPs and Mn(II) transformed from MnO2 NPs.Conclusion: Our study suggests an intelligent PVCL-based theranostic NG platform that can achieve "full-process" sensitized tumor RT under the guidance of dual-mode CT/MR imaging.
A theranostic 3D ultrasound imaging system for high resolution image-guided therapy
Authors: Hanna Bendjador, Josquin Foiret, Robert Wodnicki, Douglas N Stephens, Zoe Krut, Eun-Yeong Park, Zulma Gazit, Dan Gazit, Gadi Pelled, Katherine W Ferrara
Journal: Theranostics (2022)

Microbubble contrast agents are a diagnostic tool with broad clinical impact and an increasing number of indications. Many therapeutic applications have also been identified. Yet, technologies for ultrasound guidance of microbubble-mediated therapy are limited. In particular, arrays that are capable of implementing and imaging microbubble-based therapy in three dimensions in real-time are lacking. We propose a system to perform and monitor microbubble-based therapy, capable of volumetric imaging over a large field-of-view. To propel the promise of the theranostic treatment strategies forward, we have designed and tested a unique array and system for 3D ultrasound guidance of microbubble-based therapeutic protocols based on the frequency, temporal and spatial requirements.
The role of Jagged1 as a dynamic switch of cancer cell plasticity in PDAC assembloids
Authors: Jae-Il Choi, John Hoon Rim, Sung Ill Jang, Joon Seong Park, Hak Park, Jae Hee Cho, Jong-Baeck Lim
Journal: Theranostics (2022)

Background: Pancreatic ductal adenocarcinoma (PDAC), which commonly relapses due to chemotherapy resistance, has a poor 5-year survival rate (< 10%). The ability of PDAC to dynamically switch between cancer-initiating cell (CIC) and non-CIC states, which is influenced by both internal and external events, has been suggested as a reason for the low drug efficacy. However, cancer cell plasticity using patient-derived PDAC organoids remains poorly understood. Methods: First, we successfully differentiated CICs, which were the main components of PDAC organoids, toward epithelial ductal carcinomas. We further established PDAC assembloids of organoid-derived differentiated ductal cancer cells with endothelial cells (ECs) and autologous immune cells. To investigate the mechanism for PDAC plasticity, we performed single-cell RNA sequencing analysis after culturing the assembloids for 7 days. Results: In the PDAC assembloids, the ECs and immune cells acted as tumor-supporting cells and induced plasticity in the differentiated ductal carcinomas. We also observed that the transcriptome dynamics during PDAC re-programming were related to the WNT/beta-catenin pathway and apoptotic process. Interestingly, we found that WNT5B in the ECs was highly expressed by trans interaction with a JAG1. Furthermore, JAG1 was highly expressed on PDAC during differentiation, and NOTCH1/NOTCH2 were expressed on the ECs at the same time. The WNT5B expression level correlated positively with those of JAG1, NOTCH1, and NOTCH2, and high JAG1 expression correlated with poor survival. Additionally, we experimentally demonstrated that neutralizing JAG1 inhibited cancer cell plasticity. Conclusions: Our results indicate that JAG1 on PDAC plays a critical role in cancer cell plasticity and maintenance of tumor heterogeneity.
SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways
Authors: Li Ma, Rongjun Zou, Wanting Shi, Na Zhou, Shaoxian Chen, Hao Zhou, Xinxin Chen, Yueheng Wu
Journal: Theranostics (2022)

Background: Given the importance of microvascular injury in infarct formation and expansion, development of therapeutic strategies for microvascular protection against myocardial ischemia/reperfusion injury (IRI) is of great interest.Here, we explored the molecular mechanisms underlying the protective effects of the SGLT2 inhibitor dapagliflozin (DAPA) against cardiac microvascular dysfunction mediated by IRI.Methods: DAPA effects were evaluated both in vivo, in mice subjected to IRI, and in vitro, in human coronary artery endothelial cells (HCAECs) exposed to hypoxia/reoxygenation (H/R).DAPA pretreatment attenuated luminal stenosis, endothelial swelling, and inflammation in cardiac microvessels of IRI-treated mice.Results: In H/R-challenged HCAECs, DAPA treatment improved endothelial barrier function, endothelial nitric oxide synthase (eNOS) activity, and angiogenic capacity, and inhibited H/R-induced apoptosis by preventing cofilin-dependent F-actin depolymerization and cytoskeletal degradation.Inhibition of H/R-induced xanthine oxidase (XO) activation and upregulation, sarco(endo)plasmic reticulum calcium-ATPase 2 (SERCA2) oxidation and inactivation, and cytoplasmic calcium overload was further observed in DAPA-treated HCAECs.DAPA also suppressed calcium/Calmodulin (CaM)-dependent kinase II (CaMKII) activation and cofilin phosphorylation, and preserved cytoskeleton integrity and endothelial cell viability following H/R.Importantly, the beneficial effects of DAPA on cardiac microvascular integrity and endothelial cell survival were largely prevented in IRI-treated SERCA2-knockout mice.Conclusions: These results indicate that DAPA effectively reduces cardiac microvascular damage and endothelial dysfunction during IRI through inhibition of the XO-SERCA2-CaMKII-cofilin pathway.
Spatial maps of hepatocellular carcinoma transcriptomes reveal spatial expression patterns in tumor immune microenvironment
Authors: Yue-fan Wang, Sheng-xian Yuan, Hui Jiang, Zhi-xuan Li, Hao-zan Yin, Jian Tan, Zhi-hui Dai, Chun-mei Ge, Shu-han Sun, Fu Yang
Journal: Theranostics (2022)

Rationale: Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant disease with the complex immune microenvironment, which ultimately influence clinic outcomes of patients.However, the spatial expression patterns of diverse immune cells among tumor microenvironment remain to be further deciphered.Methods: Spatial transcriptomics sequencing (ST) was implemented on two portions of HCC specimens.Differentially expressed genes, cell cycle phases, epithelial-mesenchymal features, pseudo-time and immune infiltration analysis were applied to demonstrate the intratumor heterogeneity and define the specific immune-related regions, and the results were further validated by a second analysis on another ST study.In vitro and in vivo experiments were conducted to confirm the functional mechanisms of key molecules such as CCL15, CCL19 and CCL21.Clinical tissue samples were used to assess their potential prognostic and therapeutic values.Results: Totally, 7553 spots were categorized into 15 subsets by hierarchical clustering, and malignant subsets with intratumor heterogeneity phenotypes were identified.Spatial heterogeneity from distinct sectors highlights specific chemokines: CCL15 is remarkable in the core region of the carcinoma sector and facilitates the immunosuppressive microenvironment by recruiting and polarizing M2-like macrophages in vitro and in vivo; High expression of CCL15 and CD163 respectively predicts poor prognosis of HCC patients, and the combined application of them has better predictive value.CCL19 and CCL21, sharing similar spatial expression patterns, are highly-correlated and prominent in the immune infiltration enrichment and recruit CD3 + T cells and CD20 + B cells to inhibit the growth of HCC, indicating a good prognosis of HCC patients.Conclusions: Taken together, our studies preliminarily reveal intratumor heterogeneity of HCC based on ST techniques and unravel the previously unexplored spatial expression patterns in the immune microenvironment.We also highlight the clinical significance and spatial discrepancy of key molecules, providing novel insight for further developing therapeutic strategies in HCC.
MicroRNA-23a-3p Inhibits Mucosal Melanoma Growth and Progression through Targeting Adenylate Cyclase 1 and Attenuating cAMP and MAPK Pathways: Erratum
Authors: Meng Ma, Jie Dai, Huan Tang, Tianxiao Xu, Sifan Yu, Lu Si, Chuanliang Cui, Xinan Sheng, Zhihong Chi, Lili Mao, Xiaowen Wu, Lu Yang, Huan Yu, Siming Li, Bin Lian, Bixiang Tang, Xuan Wang, Xieqiao Yan, Xue Bai, Li Zhou, Yan Kong, Jun Guo
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.30516.].
Drug-induced self-assembled nanovesicles for doxorubicin resistance reversal via autophagy inhibition and delivery synchronism
Authors: Juan Wang, Liyan Qiu
Journal: Theranostics (2022)

Background: As a classical autophagy inhibitor, CQ has been supposed to increase the sensitivity of tumors to chemotherapeutics. However, there exists a quite huge gap between laboratory research and clinical application, which is related to the distinct pharmacokinetic behavior of CQ to a great extent. Methods: Based on amphiphilic copolymer PPAP, a pH-responsive drug-induced self-assembled nanovesicle, named DC-DIV/C, was constructed to load DOX⋅HCl and CQ. The physicochemical properties of DC-DIV/C were characterized. To validate the cooperative action and delivery synchronism of DOX⋅HCl and CQ, cytotoxicity, apoptosis, cellular uptake and autophagy assay were investigated in DOX⋅HCl resistant cancer cells. The pharmacokinetic character and antitumor effect of DC-DIV/C were evaluated on rats and nude mice bearing xenograft drug-resistant K562/ADR tumors, respectively. Results: DC-DIV/C could simultaneously encapsulate DOX·HCl and CQ at the optimal ratio of 1:2. In vitro and in vivo tests confirmed that DC-DIV/C acted as an excellent vehicle for the synchronous delivery of DOX⋅HCl and CQ during the process of blood circulation, cellular uptake and intracellular release. Furthermore, CQ accomplished autophagy inhibition to reduce the IC50 of DOX⋅HCl resistant cancer cells. Consequently, DC-DIV/C exhibited the extremely improved anti-tumor effect with 84.52% TIR on K562/ADR tumor. Conclusion: This study provides a promising and powerful strategy to achieve enhanced treatment outcomes for the precise combination therapy.
Silk fibroin-based biomaterials for cartilage/osteochondral repair
Authors: Ziyang Zhou, Jin Cui, Shunli Wu, Zhen Geng, Jiacan Su
Journal: Theranostics (2022)

Osteoarthritis (OA) is a common joint disease with a high disability rate.In addition, OA not only causes great physiological and psychological harm to patients, but also puts great pressure on the social healthcare system.Pathologically, the disintegration of cartilage and the lesions of subchondral bone are related to OA.Currently, tissue engineering, which is expected to overcome the defects of existing treatment methods, had a lot of research in the field of cartilage/osteochondral repair.Silk fibroin (SF), as a natural macromolecular material with good biocompatibility, unique mechanical properties, excellent processability and degradability, holds great potential in the field of tissue engineering.Nowadays, SF had been prepared into various materials to adapt to the demands of cartilage/osteochondral repair.SF-based biomaterials can also be functionally modified to enhance repair performance further.In this review, the preparation methods, types, structures, mechanical properties, and functional modifications of SF-based biomaterials used for cartilage/osteochondral repair are summarized and discussed.We hope that this review will provide a reference for the design and development of SF-based biomaterials in cartilage/osteochondral repair field.
Biomechanical microenvironment in peripheral nerve regeneration: from pathophysiological understanding to tissue engineering development
Authors: Lingchi Kong, Xin Gao, Yun Qian, Wei Sun, Zhengwei You, Cunyi Fan
Journal: Theranostics (2022)

Peripheral nerve injury (PNI) caused by trauma, chronic disease and other factors may lead to partial or complete loss of sensory, motor and autonomic functions, as well as neuropathic pain.Biological activities are always accompanied by mechanical stimulation, and biomechanical microenvironmental homeostasis plays a complicated role in tissue repair and regeneration.Recent studies have focused on the effects of biomechanical microenvironment on peripheral nervous system development and function maintenance, as well as neural regrowth following PNI.For example, biomechanical factors-induced cluster gene expression changes contribute to formation of peripheral nerve structure and maintenance of physiological function.In addition, extracellular matrix and cell responses to biomechanical microenvironment alterations after PNI directly trigger a series of cascades for the well-organized peripheral nerve regeneration (PNR) process, where cell adhesion molecules, cytoskeletons and mechanically gated ion channels serve as mechanosensitive units, mechanical effector including focal adhesion kinase (FAK) and yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) as mechanotransduction elements.With the rapid development of tissue engineering techniques, a substantial number of PNR strategies such as aligned nerve guidance conduits, three-dimensional topological designs and piezoelectric scaffolds emerge expected to improve the neural biomechanical microenvironment in case of PNI.These tissue engineering nerve grafts display optimized mechanical properties and outstanding mechanomodulatory effects, but a few bottlenecks restrict their application scenes.In this review, the current understanding in biomechanical microenvironment homeostasis associated with peripheral nerve function and PNR is integrated, where we proposed the importance of balances of mechanosensitive elements, cytoskeletal structures, mechanotransduction cascades, and extracellular matrix components; a wide variety of promising tissue engineering strategies based on biomechanical modulation are introduced with some suggestions and prospects for future directions.
The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response
Authors: Francisco J. Enguita, Ana Lúcia Leitão, J. Tyson McDonald, Viktorija Zaksas, Saswati Das, Diego Galeano, Deanne Taylor, Eve Syrkin Wurtele, Amanda Saravia-Butler, Stephen B. Baylin, Robert Meller, D. Marshall Porterfield, Douglas C. Wallace, Jonathan C. Schisler, Christopher E. Mason, Afshin Beheshti
Journal: Theranostics (2022)

Rationale: Viral infections are complex processes based on an intricate network of molecular interactions. The infectious agent hijacks components of the cellular machinery for its profit, circumventing the natural defense mechanisms triggered by the infected cell. The successful completion of the replicative viral cycle within a cell depends on the function of viral components versus the cellular defenses. Non-coding RNAs (ncRNAs) are important cellular modulators, either promoting or preventing the progression of viral infections. Among these ncRNAs, the long non-coding RNA (lncRNA) family is especially relevant due to their intrinsic functional properties and ubiquitous biological roles. Specific lncRNAs have been recently characterized as modulators of the cellular response during infection of human host cells by single stranded RNA viruses. However, the role of host lncRNAs in the infection by human RNA coronaviruses such as SARS-CoV-2 remains uncharacterized. Methods: In the present work, we have performed a transcriptomic study of a cohort of patients with different SARS-CoV-2 viral load and analyzed the involvement of lncRNAs in supporting regulatory networks based on their interaction with RNA-binding proteins (RBPs). Results: Our results revealed the existence of a SARS-CoV-2 infection-dependent pattern of transcriptional up-regulation in which specific lncRNAs are an integral component. To determine the role of these lncRNAs, we performed a functional correlation analysis complemented with the study of the validated interactions between lncRNAs and RBPs. This combination of in silico functional association studies and experimental evidence allowed us to identify a lncRNA signature composed of six elements - NRIR, BISPR, MIR155HG, FMR1-IT1, USP30-AS1, and U62317.2 - associated with the regulation of SARS-CoV-2 infection. Conclusions: We propose a competition mechanism between the viral RNA genome and the regulatory lncRNAs in the sequestering of specific RBPs that modulates the interferon response and the regulation of RNA surveillance by nonsense-mediated decay (NMD).
Lactate metabolism coordinates macrophage response and regeneration in zebrafish
Authors: Candice Bohaud, Jholy De La Cruz, Claudia Terraza, Audrey Barthelaix, Béryl Laplace-Builhé, Christian Jorgensen, Yoan Arribat, Farida Djouad
Journal: Theranostics (2022)

Rationale: Macrophages are multifunctional cells with a pivotal role on tissue development, homeostasis and regeneration. Indeed, in response to tissue injury and the ensuing regeneration process, macrophages are challenged and undergo massive metabolic adaptations and changes. However, the control of this metabolic reprogramming by macrophage microenvironment has never been deciphered in vivo. Methods: In this study, we used zebrafish model and caudal fin resection as a robust regeneration system. We explored specific changes in gene expression after tissue amputation via single-cell RNA sequencing analysis and whole-tissue transcriptomic analysis. Based on the identification of key modifications, we confirmed the role of the lactate pathway in macrophage response and fin regeneration, through the combination of chemical and genetic inhibitors of this pathway. Results: Single cell RNA sequencing revealed the upregulation of different genes associated with glycolysis and lactate metabolism in macrophages, upon fin regeneration. Hence, using chemical inhibitors of the LDH enzyme, we confirmed the role of lactate in macrophage recruitment and polarization, to promote a pro-inflammatory phenotype and enhance fin regeneration. The genetic modulation of monocarboxylate transporters illustrated a complex regulation of lactate levels, based on both intracellular and extracellular supplies. Commonly, the different sources of lactate resulted in macrophage activation with an increased expression level of inflammatory cytokines such as TNFa during the first 24 hours of regeneration. Transcriptomic analyses confirmed that lactate induced a global modification of gene expression in macrophages. Conclusion: Altogether, our findings highlight the crucial role of lactate at the onset of macrophage differentiation toward a pro-inflammatory phenotype. The deep modifications of macrophage phenotype mediated by lactate and downstream effectors play a key role to coordinate inflammatory response and tissue regeneration.
Bioactive antibacterial silica-based nanocomposites hydrogel scaffolds with high angiogenesis for promoting diabetic wound healing and skin repair: Erratum
Authors: Yannan Li, Tianzhen Xu, Zhuolong Tu, Wentong Dai, Yumeng Xue, Chengxuan Tang, Weiyang Gao, Cong Mao, Bo Lei, Cai Lin
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.41839.].
Mecp2 protects kidney from ischemia-reperfusion injury through transcriptional repressing IL-6/STAT3 signaling
Authors: Jiao Wang, Mingrui Xiong, Yu Fan, Chengyu Liu, Qing Wang, Dong Yang, Yangmian Yuan, Yixue Huang, Shun Wang, Yu Zhang, Shuxuan Niu, Junqiu Yue, Hua Su, Chun Zhang, Hong Chen, Ling Zheng, Kun Huang
Journal: Theranostics (2022)

Rationale: Ischemia-reperfusion (IR) induced acute kidney injury (AKI) causes serious clinical problems associated with high morbidity and mortality. Mecp2 is a methyl-CpG binding protein, its mutation or deletion causes a neurodevelopment disease called Rett syndrome. Notably, some Rett syndrome patients present urological dysfunctions. It remains unclear whether and how Mecp2 affects AKI. Methods: Renal tubular cell specific Mecp2 deletion mice challenged with IR injury were used to investigate the effects of Mecp2 on renal tubular damage, function, cell death, fibrosis and inflammation. Cultured renal epithelial cell lines were transfected with wildtype or different domain-deletion mutants of Mecp2 to study the effects of Mecp2 on Il-6/STAT3 signaling. Results: Our results indicated rapidly upregulated Mecp2 upon acute in vivo and in vitro renal injury. Notably, increased tubular MeCP2 staining was also found in the renal sections of AKI patients. Furthermore, ablation of Mecp2 aggravated renal injury, and promoted renal cell death, inflammation, and fibrosis. Mechanistically, through its transcriptional repression domain, Mecp2 bound to the promoter of proinflammatory cytokine Il-6 to negatively regulate its expression, thus inhibiting STAT3 activation. Conclusions: A novel protective role of Mecp2 against AKI via repressing the Il-6/STAT3 axis was suggested.